Lysosomal Biology Research Articles

Autophagy Deficits Underly Selective Neuronal Vulnerability to Alpha Synuclein Fibrils in Alzheimer’s and Parkinson’s iPSC Derived Neurons

AbstractBackgroundAlzheimer’s (AD) and Parkinson’s disease (PD) feature progressive neurodegeneration in a remarkably regionally selective manner. Post mortem studies have posited a role for cell autonomous mechanisms driving this, so we aimed to examine a live human induced pluripotent stem cell (iPSC) model to see whether it can replicate the phenomenon of selective neuronal vulnerability, so to better determine disease mechanisms and therapeutic targets.MethodiPSC‐derived neurons offer a rare opportunity to examine cell autonomous vulnerability in live human cells. iPSCs from patients with AD‐related presenilin‐1 mutations (n = 6), PD‐related leucine rich repeat kinase 2 mutations (n = 6), and isogenic corrected (n = 4) and healthy controls (n = 4) have been differentiated into both cortical and midbrain dopaminergic neurons to enable comparison of pre‐formed fibril induced pathology in different neuronal subtypes from the same patient. We then examined lysosomal number, morphology, degradation, pH, and calcium using live imaging assays, alongside mitochondrial biology, and electrophysiology to understand underlying drivers of vulnerability in the cell types.ResultUpon insult with alpha‐synuclein PFFs, AD and PD dopaminergic neurons produce substantial Lewy‐like pathology, whereas cortical neurons remain relatively resilient to alpha‐synuclein aggregation, suggesting cell‐type vulnerability. PSEN1‐Intron‐4‐Deletion cortical neurons, however, had significantly elevated pathology. These lines displayed hyperactivity on microelectrode arrays and abnormal lysosomal biology, including increased LAMP1 and dysregulated calcium. PFF‐insulted AD cortical neurons also have impaired neurite outgrowth, while PD cortical neurons are resilient.ConclusionThese preliminary results show relative vulnerability of AD against PD cortical neurons, and dopaminergic against cortical neurons to alpha‐synuclein aggregates for the first time. These suggest the selective vulnerability to proteinopathy in these diseases is reflected by the iPSC neuronal model and support the notion that cell intrinsic factors like autophagy drive vulnerability.

Cell-Type Resolved Protein Atlas of Brain Lysosomes Identifies SLC45A1-Associated Disease as a Lysosomal Disorder.

Mutations in lysosomal genes cause neurodegeneration and neurological lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of the lysosome from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of novel lysosomal proteins and reveal the diversity of the lysosomal composition across brain cell types. Notably, we discovered SLC45A1, mutations in which cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. Mechanistically, SLC45A1 plays a dual role in lysosomal sugar transport and stabilization of V1 subunits of the V-ATPase. SLC45A1 deficiency depletes the V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as a LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution in the brain and its implications for neurodegeneration.

Discovery of a novel near-infrared triphenylamine-dicyanoisophorone fluorescent probe with a large Stokes shift for long-term tracking of lysosomes in live cells

Fluorescent probes are powerful tools for real-time tracking of lysosomal movements and spatial distribution, which appears to be essential for understanding the biology of lysosomes. However, the commercially used lysosomal trackers exhibited some limitations, such as narrow Stokes shifts, poor photostability, and green to red instead of near-infrared (NIR) emission. In this study, we have developed a fluorescent probe by incorporating the triphenylamine fragment into the dicyanoisophorone fluorophore. This probe displayed impressive NIR emission (centered at 755 nm) and remarkable Stokes shift (235 nm), which was then demonstrated to be insensitive to lysosomal pH as well as viscosity, and expressed long-term lysosomal tracking ability with little cytotoxicity in live cells. Altogether, this study provided an ideal NIR fluorescent probe for lysosomal tracking.

Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis.

Lysosomes have a central role in the disposal of extracellular and intracellular cargo and also function as metabolic sensors and signalling platforms in the immunometabolic reprogramming of macrophages and other immune cells in atherosclerosis. Lysosomes can rapidly sense the presence of nutrients within immune cells, thereby switching from catabolism of extracellular material to the recycling of intracellular cargo. Such a fine-tuned degradative response supports the generation of metabolic building blocks through effectors such as mTORC1 or TFEB. By coupling nutrients to downstream signalling and metabolism, lysosomes serve as a crucial hub for cellular function in innate and adaptive immune cells. Lysosomal dysfunction is now recognized to be a hallmark of atherogenesis. Perturbations in nutrient-sensing and signalling have profound effects on the capacity of immune cells to handle cholesterol, perform phagocytosis and efferocytosis, and limit the activation of theinflammasome and other inflammatory pathways. Strategies to improve lysosomal function hold promise as novel modulators of the immunoinflammatory response associated with atherosclerosis. In this Review, we describe the crosstalk between lysosomal biology and immune cell function and polarization, with a particular focus on cellular immunometabolic reprogramming in the context of atherosclerosis.

Protonation regulates intermolecular interaction force to achieve reversible ACQ-AIE conversion

In recent years, there has been a lot of focus on aggregation-induced emission materials, and most of the research has focused on the unidirectional conversion from ACQ (aggregation-causing quenching) to AIE (aggregation-induced emission), which inevitably requires complex chemical synthesis and cumbersome processes, and molecules with reversible ACQ and AIE conversion characteristics are rarely reported. In order to achieve a reversible conversion based on a single material between ACQ and AIE properties, we have developed a new functional material, DBPZ-2 (1,4-bis((4-(benzo[c] (Li et al., 2020; Hu et al., 2014; Song et al., 2024) [1,2,5]thiadiazol-4-yl)piperazin-1-yl)methyl)benzene). This compound exhibits AIE properties under neutral conditions, and interestingly, it exhibits significant ACQ properties when protonated, and then restores AIE properties after simple deprotonation. Furthermore, the sensitive response of DBPZ-2 to pH can be used as a fluorescent probe to monitor the changes in the pH value of cellular lysosomes, which brings hopes for future research on lysosomal biology and related diseases.

Discovery of the Lysosome-Inhibiting Function of Acremolactone B

Lysosome inhibitors have garnered considerable interest for their utility in lysosome biology research and potential therapeutic applications. We discovered the lysosome-inhibiting function of acremolactone B (1), a scarce azaphilone-type polyketide, leveraging our previous scalable synthesis. This compound significantly reduces lysosomal acidity and impairs the maturation of the lysosomal protease cathepsin D (CTSD) in triple-negative breast cancer cells (MDA-MB-231) and human lung cancer cells (A549). Furthermore, we found that compound 1 suppresses downstream autophagy, as revealed by monitoring autophagic flux and conducting transmission electron microscopy (TEM) analysis. This study unveils the previously unrecognized biological role of 1 and introduces a new scaffold for lysosome inhibitors.

Exploring lysosomal biology: current approaches and methods.

Lysosomes are the degradation centers and signaling hubs in the cell. Lysosomes undergo adaptation to maintain cell homeostasis in response to a wide variety of cues. Dysfunction of lysosomes leads to aging and severe diseases including lysosomal storage diseases (LSDs), neurodegenerative disorders, and cancer. To understand the complexity of lysosome biology, many research approaches and tools have been developed to investigate lysosomal functions and regulatory mechanisms in diverse experimental systems. This review summarizes the current approaches and tools adopted for studying lysosomes, and aims to provide a methodological overview of lysosomal research and related fields.

Roles of neuronal lysosomes in the etiology of Parkinson's disease.

Therapeutic progress in neurodegenerative conditions such as Parkinson's disease has been hampered by a lack of detailed knowledge of its molecular etiology. The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes involved in the onset of disease. In this respect, the autophagy-lysosome system has emerged in recent years as a strong point of convergence for genetics, genomics, and pathologic indications, spanning both familial and idiopathic Parkinson's disease. Most, if not all, genes linked to familial disease are involved, in a regulatory capacity, in lysosome function (e.g., LRRK2, alpha-synuclein, VPS35, Parkin, and PINK1). Moreover, the majority of genomic loci associated with increased risk of idiopathic Parkinson's cluster in lysosome biology and regulation (GBA as the prime example). Lastly, neuropathologic evidence showed alterations in lysosome markers in autoptic material that, coupled to the alpha-synuclein proteinopathy that defines the disease, strongly indicate an alteration in functionality. In this Brief Review article, I present a personal perspective on the molecular and cellular involvement of lysosome biology in Parkinson's pathogenesis, aiming at a larger vision on the events underlying the onset of the disease. The attempts at targeting autophagy for therapeutic purposes in Parkinson's have been mostly aimed at "indiscriminately" enhancing its activity to promote the degradation and elimination of aggregate protein accumulations, such as alpha-synuclein Lewy bodies. However, this approach is based on the assumption that protein pathology is the root cause of disease, while pre-pathology and pre-degeneration dysfunctions have been largely observed in clinical and pre-clinical settings. In addition, it has been reported that unspecific boosting of autophagy can be detrimental. Thus, it is important to understand the mechanisms of specific autophagy forms and, even more, the adjustment of specific lysosome functionalities. Indeed, lysosomes exert fine signaling capacities in addition to their catabolic roles and might participate in the regulation of neuronal and glial cell functions. Here, I discuss hypotheses on these possible mechanisms, their links with etiologic and risk factors for Parkinson's disease, and how they could be targeted for disease-modifying purposes.

Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient neurons

BackgroundProgranulin (PGRN) is a lysosomal glycoprotein implicated in various neurodegenerative diseases, including frontotemporal dementia and neuronal ceroid lipofuscinosis. Over 70 mutations discovered in the GRN gene all result in reduced expression of the PGRN protein. Genetic and functional studies point toward a regulatory role for PGRN in lysosome functions. However, the detailed molecular function of PGRN within lysosomes and the impact of PGRN deficiency on lysosomes remain unclear.MethodsWe developed multifaceted proteomic techniques to characterize the dynamic lysosomal biology in living human neurons and fixed mouse brain tissues. Using lysosome proximity labeling and immuno-purification of intact lysosomes, we characterized lysosome compositions and interactome in both human induced pluripotent stem cell (iPSC)-derived glutamatergic neurons (i3Neurons) and mouse brains. Using dynamic stable isotope labeling by amino acids in cell culture (dSILAC) proteomics, we measured global protein half-lives in human i3Neurons for the first time.ResultsLeveraging the multi-modal proteomics and live-cell imaging techniques, we comprehensively characterized how PGRN deficiency changes the molecular and functional landscape of neuronal lysosomes. We found that PGRN loss impairs the lysosome’s degradative capacity with increased levels of v-ATPase subunits on the lysosome membrane, increased hydrolases within the lysosome, altered protein regulations related to lysosomal transport, and elevated lysosomal pH. Consistent with impairments in lysosomal function, GRN-null i3Neurons and frontotemporal dementia patient-derived i3Neurons carrying GRN mutation showed pronounced alterations in protein turnover, such as cathepsins and proteins related to supramolecular polymerization and inherited neurodegenerative diseases.ConclusionThis study suggested PGRN as a critical regulator of lysosomal pH and degradative capacity, which influences global proteostasis in neurons. Beyond the study of progranulin deficiency, these newly developed proteomic methods in neurons and brain tissues provided useful tools and data resources for the field to study the highly dynamic neuronal lysosome biology.Graphical

The progranulin cleavage product granulin 3 exerts a dominant negative effect on animal fitness.

Progranulin is an evolutionarily conserved protein that has been implicated in human neurodevelopmental and neurodegenerative diseases. Human progranulin is comprised of multiple cysteine-rich, biologically active granulin peptides. Granulin peptides accumulate with age and stress, however their functional contributions relative to full-length progranulin remain unclear. To address this, we generated C. elegans strains that produced quantifiable levels of both full-length progranulin/PGRN-1 protein and cleaved granulin peptide. Using these strains, we demonstrated that even in the presence of intact PGRN-1, granulin peptides suppressed the activity of the lysosomal aspartyl protease activity, ASP-3/CTSD. Granulin peptides were also dominant over PGRN-1 in compromising animal fitness as measured by progress through development and stress response. Finally, the degradation of human TDP-43 was impaired when the granulin to PGRN-1 ratio was increased, representing a disease-relevant downstream impact of impaired lysosomal function. In summary, these studies suggest that not only absolute progranulin levels, but also the balance between full-length progranulin and its cleavage products, is important in regulating lysosomal biology. Given its relevance in human disease, this suggests that the processing of progranulin into granulins should be considered as part of disease pathobiology and may represent a site of therapeutic intervention.

Eat, prey, love: Pathogen-mediated subversion of lysosomal biology.

The mammalian lysosome is classically considered the 'garbage can' of the cell, contributing to clearance of infection through its primary function as a degradative organelle. Intracellular pathogens have evolved several strategies to evade contact with this harsh environment through subversion of endolysosomal trafficking or escape into the cytosol. Pathogens can also manipulate pathways that lead to lysosomal biogenesis or alter the abundance or activity of lysosomal content. This pathogen-driven subversion of lysosomal biology is highly dynamic and depends on a range of factors, including cell type, stage of infection, intracellular nicheand pathogen load. The growing body of literature in this field highlights the nuanced and complex relationship between intracellular pathogens and the host lysosome, which is critical for our understanding of infection biology.

Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel

Maintaining a highly acidic lysosomal pH is central to cellular physiology. Here, we use functional proteomics, single-particle cryo-EM, electrophysiology, and invivo imaging to unravel a key biological function of human lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in regulating lysosomal pH homeostasis. Despite being widely used as a lysosomal marker, the physiological functions of the LAMP proteins have long been overlooked. We show that LAMP-1 and LAMP-2 directly interact with and inhibit the activity of the lysosomal cation channel TMEM175, a key player in lysosomal pH homeostasis implicated in Parkinson's disease. This LAMP inhibition mitigates the proton conduction of TMEM175 and facilitates lysosomal acidification to a lower pH environment crucial for optimal hydrolase activity. Disrupting the LAMP-TMEM175 interaction alkalinizes the lysosomal pH and compromises the lysosomal hydrolytic function. In light of the ever-increasing importance of lysosomes to cellular physiology and diseases, our data have widespread implications for lysosomal biology.

Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia.

Loss-of-function heterozygous mutations in GRN, the gene encoding progranulin (PGRN), were identified in patients with frontotemporal lobar degeneration (FTLD) almost two decades ago and are generally linked to reduced PGRN protein expression levels. Although initial characterization of PGRN function primarily focused on its role in extracellular signaling as a secreted protein, more recent studies revealed critical roles of PGRN in regulating lysosome function, including proteolysis and lipid degradation, consistent with its lysosomal localization. Emerging from these studies is the notion that PGRN regulates glucocerebrosidase activity via direct chaperone activities and via interaction with prosaposin (i.e., a key regulator of lysosomal sphingolipid-metabolizing enzymes), as well as with the anionic phospholipid bis(monoacylglycero)phosphate. This emerging lysosomal biology of PGRN identified novel and promising opportunities in therapeutic discovery as well as biomarker development.

Enhancement of lysosome biogenesis as a potential therapeutic approach for neurodegenerative diseases.

Millions of people are suffering from Alzheimer's disease globally, but there is still no effective treatment for this neurodegenerative disease. Thus, novel therapeutic approaches for Alzheimer's disease are needed, which requires further evaluation of the regulatory mechanisms of protein aggregate degradation. Lysosomes are crucial degradative organelles that maintain cellular homeostasis. Transcription factor EB-mediated lysosome biogenesis enhances autolysosome-dependent degradation, which subsequently alleviates neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. In this review, we start by describing the key features of lysosomes, including their roles in nutrient sensing and degradation, and their functional impairments in different neurodegenerative diseases. We also explain the mechanisms - especially the post-translational modifications - which impact transcription factor EB and regulate lysosome biogenesis. Next, we discuss strategies for promoting the degradation of toxic protein aggregates. We describe Proteolysis-Targeting Chimera and related technologies for the targeted degradation of specific proteins. We also introduce a group of LYsosome-Enhancing Compounds, which promote transcription factor EB-mediated lysosome biogenesis and improve learning, memory, and cognitive function in APP-PSEN1 mice. In summary, this review highlights the key aspects of lysosome biology, the mechanisms of transcription factor EB activation and lysosome biogenesis, and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.

The Biology of Lysosomes: From Order to Disorder.

Since its discovery in 1955, the understanding of the lysosome has continuously increased. Once considered a mere waste removal system, the lysosome is now recognised as a highly crucial cellular component for signalling and energy metabolism. This notable evolution raises the need for a summarized review of the lysosome's biology. As such, throughout this article, we will be compiling the current knowledge regarding the lysosome's biogenesis and functions. The comprehension of this organelle's inner mechanisms is crucial to perceive how its impairment can give rise to lysosomal disease (LD). In this review, we highlight some examples of LD fine-tuned mechanisms that are already established, as well as others, which are still under investigation. Even though the understanding of the lysosome and its pathologies has expanded through the years, some of its intrinsic molecular aspects remain unknown. In order to illustrate the complexity of the lysosomal diseases we provide a few examples that have challenged the established single gene-single genetic disorder model. As such, we believe there is a strong need for further investigation of the exact abnormalities in the pathological pathways in lysosomal disease.

Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation.

Disruption to protein homeostasis caused by lysosomal dysfunction and associated impairment of autophagy is a prominent pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The most common genetic cause of ALS/FTD is a G4C2 hexanucleotide repeat expansion in C9orf72 (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 repeat transcripts gives rise to dipeptide repeat (DPR) proteins that have been shown to be toxic and may contribute to disease etiology. Genetic variants in TMEM106B have been associated with frontotemporal lobar degeneration with TDP-43 pathology and disease progression in C9ALS/FTD. TMEM106B encodes a lysosomal transmembrane protein of unknown function that is involved in various aspects of lysosomal biology. How TMEM106B variants affect C9ALS/FTD is not well understood but has been linked to changes in TMEM106B protein levels. Here, we investigated TMEM106B function in the context of C9ALS/FTD DPR pathology. We report that knockdown of TMEM106B expression exacerbates the accumulation of C9ALS/FTD-associated cytotoxic DPR proteins in cell models expressing RAN-translated or AUG-driven DPRs as well as in C9ALS/FTD-derived iAstrocytes with an endogenous G4C2 expansion by impairing autophagy. Loss of TMEM106B caused a block late in autophagy by disrupting autophagosome to autolysosome maturation which coincided with impaired lysosomal acidification, reduced cathepsin activity, and juxtanuclear clustering of lysosomes. Lysosomal clustering required Rab7A and coincided with reduced Arl8b-mediated anterograde transport of lysosomes to the cell periphery. Increasing Arl8b activity in TMEM106B-deficient cells not only restored the distribution of lysosomes, but also fully rescued autophagy and DPR protein accumulation. Thus, we identified a novel function of TMEM106B in autophagosome maturation via Arl8b. Our findings indicate that TMEM106B variants may modify C9ALS/FTD by regulating autophagic clearance of DPR proteins. Caution should therefore be taken when considering modifying TMEM106B expression levels as a therapeutic approach in ALS/FTD.

The endo-lysosomal regulatory protein BLOC1S1 modulates hepatic lysosomal content and lysosomal lipolysis

BLOC1S1 is a common component of BLOC and BORC multiprotein complexes which play distinct roles in endosome and lysosome biology. Recent human mutations in BLOC1S1 associate with juvenile leukodystrophy. As leukodystrophy is linked to perturbed lysosomal lipid storage we explored whether BLOC1S1 itself modulates this biology. Given the central role of the liver in lipid storage, our investigations were performed in hepatocyte specific liver bloc1s1 knockout (LKO) mice and in human hepatocyte-like lines (HLCs) derived from inducible pluripotential stem cells (iPSCs) from a juvenile leukodystrophy subject's with bloc1s1 mutations and from isogenic corrected iPSCs. Here we show that hepatocyte lipid stores are diminished in parallel with increased lysosomal content, increased lysosomal lipid uptake and lipolysis in LKO mice. The lysosomal lipolysis program was independent of macro- and chaperone-mediated lipophagy but dependent on cellular lysosome content. In parallel, genetic induction of lysosomal biogenesis in a transformed hepatocyte cell line replicated depletion of intracellular lipid stores. Interestingly bloc1s1 mutant and isogenic corrected HLCs both showed normal lysosomal enzyme activity. However, relative to the isogenic corrected HLCs, mutant bloc1s1 HLCs showed reduced lysosomal content and increased lipid storage. Together these data show distinct phenotypes in human mutant HLCs compared to murine knockout cells. At the same time, human blcs1s1 mutation and murine hepatocyte bloc1s1 depletion disrupt lysosome content and the cellular lipid storage. These data support that BLOC1S1 modulates lysosome content and lipid handling independent of autophagy and show that lysosomal lipolysis is dependent on the cellular content of functional lysosomes.

Lysosome signaling in cell survival and programmed cell death for cellular homeostasis.

Recent developments in lysosome biology have transformed our view of lysosomes from static garbage disposals that can also act as suicide bags to decidedly dynamic multirole adaptive operators of cellular homeostasis. Lysosome-governed signaling pathways, proteins, and transcription factors equilibrate the rate of catabolism and anabolism (autophagy to lysosomal biogenesis and metabolite pool maintenance) by sensing cellular metabolic status. Lysosomes also interact with other organelles by establishing contact sites through which they exchange cellular contents. Lysosomal function is critically assessed by lysosomal positioning and motility for cellular adaptation. In this setting, mechanistic target of rapamycin kinase (MTOR) is the chief architect of lysosomal signaling to control cellular homeostasis. Notably, lysosomes can orchestrate explicit cell death mechanisms, such as autophagic cell death and lysosomal membrane permeabilization-associated regulated necrotic cell death, to maintain cellular homeostasis. These lines of evidence emphasize that the lysosomes serve as a central signaling hub for cellular homeostasis.

Abstract 10096: Genetic Control of Lysosomal Dysfunction Reprograms Sterol Metabolism in Pulmonary Arterial Hypertension

Background : Vascular inflammation critically regulates endothelial pathophenotypes, yet causative mechanisms remain incompletely defined, particularly in pulmonary arterial hypertension (PAH). Immune dysregulation and metabolic reprogramming are recognized tenets of PAH pathogenesis, but a unifying theory connecting the two has not been established. Methods & Results: Guided by an unbiased, metabolome-wide association study from the multicenter PAH Biobank cohort (N=2,666) that identified a proinflammatory sterol and bile acid metabolite plasma signature significantly associated with PAH mortality (adjusted P values<1.1x10 -6 ), we found in pulmonary arterial endothelial cells (ECs) that induction of the nuclear receptor coactivator 7 (NCOA7) tempered the generation of proinflammatory sterols by bolstering lysosomal acidification and constraining EC immunoactivation. Conversely, reduced NCOA7 promoted lysosomal dysfunction, resulting in sterol- and bile acid-driven inflammation and EC phenotypes consistent with PAH. Notably, the common variant intronic SNP rs11154337 in NCOA7 was found to control NCOA7 levels, lysosome activity, sterol and bile acid production, and EC immunoactivation in isogenic, CRISPR-Cas9, SNP-edited, iPSC-derived ECs, indicating a potentially widespread genetic predisposition to NCOA7 deficiency. Correspondingly, SNP rs11154337 was associated with PAH severity as noted by six-minute walk distance ( P =0.0130, β=58.15, 95% CI [14.45-119.36]) and mortality ( P =0.0250; hazard ratio=0.4368, 95% CI [0.21-0.90]) in an independent, single-center PAH cohort (N=93). In vivo , mice deficient for Ncoa7 or treated with exogenous 7α-hydroxy-3-oxo-4-cholestenoic acid (7HOCA)—chosen as a representative metabolite from the sterol signature associated with mortality in the PAH Biobank—demonstrated worsened hemodynamic and histological indices of PAH. Conclusions: Our work establishes a genetic and metabolic paradigm that links lysosomal biology and sterol and bile acid processes with EC inflammation. This paradigm carries broad implications not only on molecular diagnostic and therapeutic development in PAH but also in other vascular disorders dependent upon acquired and innate immune regulation.

Meet the First Authors.

HomeCirculation ResearchVol. 131, No. 10Meet the First Authors Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBMeet the First Authors Originally published27 Oct 2022https://doi.org/10.1161/RES.0000000000000580Circulation Research. 2022;131:790–791Sox17 Deficiency Promotes PAH via c-Met Activation (p 792)Download figureDownload PowerPointDr Chan Soon Park is a clinical fellow in the Division of Cardiology at Seoul National University Hospital (SNUH). He earned his BS and MS in Medicine from Seoul National University and his PhD in Medical Science and Engineering from Korea Advanced Institute of Science and Technology (KAIST). During the PhD program in Graduate School of Medical Science and Engineering in KAIST, he was able to learn basic and translational research, the importance of which has been increasingly emphasized in the development of novel and clinically relevant therapeutic strategies in the field of cardiology. Dr Park continues to expand his research in the roles of endothelial cells in various cardiovascular diseases (CVDs) beyond pulmonary arterial hypertension. He also has interests in clinical research, including the association between metabolic profiles and CVDs as well as the role of imaging in CVD risk stratification. Outside of work, he enjoys hiking and spending time with his family.Prohibitin2 Maintains VSMC Contractile Phenotype (p 807)Download figureDownload PowerPointDr Yiting Jia is a postdoctoral fellow at Peking University Health Science Center (PI: Dr Wei Kong and Dr Caihong Yun). He earned his PhD from Peking University. His early experience in research was focused on metabolism reprogramming, lysosome biology and cardiovascular diseases. Now he is gearing up to become an independent research investigator. Outside of work, he enjoys soccer, tennis and listening to music.Download figureDownload PowerPointDr Chenfeng Mao is a research associate at the Beijing Institute of Biotechnology in Beijing, China. He earned a PhD in human physiology from the Department of Physiology and Pathophysiology in Peking University (mentor, Dr Wei Kong). His research focuses on extracellular matrix microenvironment on vascular remodeling during physiological and disease state. Outside of work he enjoys playing badminton.MED1, BMP/TGF-β and Pulmonary Hypertension (p 828)Download figureDownload PowerPointDr Chen Wang earned her PhD from Xi’ an Jiaotong University. During her PhD studies, she was also trained in the laboratory of Dr Ingrid Fleming at the Institute of Vascular Research, Goethe University. Her research focuses on endothelial dysfunction involved in vascular diseases. She was awarded the “Paul Dudley White International Scholar” from ATVB in 2022 and has published several first-author papers including in Circulation and Circulation Research. Her career goal is to become a physician scientist working on cardiovascular diseases and related translational research. Outside of work, she enjoys traveling, music and baking.Download figureDownload PowerPointYuanming Xing is a PhD candidate in internal medicine at Xi’an Jiaotong University. She also studied computational biology at Warshel Institute for Computational Biology at the Chinese University of Hong Kong-Shenzhen. She is interested in endothelial function in cardiovascular diseases and has published several papers in the related fields. Her career plan is to become a physician who is also proficient in computational biology. She enjoys learning new things, especially what she may not be good at. In her spare time, she has a passion for animal rescue, computer programming and painting.Intrapericardial Exosomes Repair Heart via Foxo3 (p e135)Download figureDownload PowerPointDr Dashuai Zhu is a postdoctoral research fellow in the BioTherapeutics Lab, headed by Dr Ke Cheng (UNC Chapel Hill and North Carolina State University). Dashuai earned his PhD from the Nankai University, China, where he started his career on cardiac repair using tissue engineering and biomedical engineering approaches. His research focuses on regenerative medicine approaches for the treatment of heart disease, with a particular interest in cell and cell-free therapies for myocardial infarction and heart failure. He can be found on Twitter @das_zhu.Download figureDownload PowerPointDr Ke Huang is an assistant research professor in the Department of Molecular Biomedical Sciences at North Carolina State University. He earned his MD in 2008 from Shanxi Medical University and PhD from North Carolina State University. His postdoctral training was at Duke University. His research focuses on regenerative medicine strategies with a particular interest in adult stem cells, biomaterials and nanomedicine approaches. He can be found on [email protected] Previous Back to top Next FiguresReferencesRelatedDetails October 28, 2022Vol 131, Issue 10 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000580PMID: 36302055 Originally publishedOctober 27, 2022 PDF download Advertisement SubjectsAgingCardiovascular DiseaseExercise